Determinants of Isotype-Specific Germinal Center B cell Selection and Plasma Cell Longevity

Determinants of Isotype-Specific Germinal Center B cell Selection and Plasma Cell Longevity

Dr Dinis Calado; Senior Group Leader, Francis Crick Institute

Dinis Calado did his PhD at The Gulbenkian Institute (Oeiras, Portugal) under the supervision of Dr. Matthias Haury (currently at the Chan Zuckberg Imaging Institute) where he investigated the regulation of anti-inflammatory cytokines in the immune system. For his postdoctoral work Dinis joined Harvard Medical School (Boston, USA) and later the Max Debrueck Center (Berlin, Germany) where under the supervision of Prof. Klaus Rajewsky he studied the function of microRNAs, B cell receptor signalling, and mechanisms of lymphomagenesis (Diffuse Large B cell and Burkitt Lymphoma), including the role of BLIMP1 as a tumour suppressor. During his postdoctoral work Dinis also investigated germinal center (GC) B cell selection, having identified in vivo subpopulations of GC B cells with high expression of the protooncogene MYC that represent positively selected cells in physiology and that may be at a particularly high risk for malignant transformation. At The Francis Crick Institute (London, UK) Dinis and his team have determined cell clusters, within positively selected GC B cells, that are enriched for memory B cells, plasma cells and recycling cells; they also identified the role of MYC/MIZ1 complexes in the restriction of memory B cell differentiation and of MIZ1 in protecting IgG1 B cells from cell death during positive selection, and have generated the first genetically engineered mouse allowing specific genetic manipulation of plasma cells in vivo in their niche.

Antibody-mediated immunity is critical for infection control and vaccination efficacy. In this seminar, we will discuss the pivotal role of germinal center reactions in orchestrating the transition from IgM to high-affinity IgG antibodies, elucidating the molecular mechanisms guiding isotype-specific selection within these reactions. Our research of this crucial aspect of humoral immunity regulation within germinal centers not only enhances our understanding of immune-related pathologies but also opens new avenues for refining vaccination strategies. Additionally, we examine long-lived plasma cells, indispensable for sustained humoral protection, utilizing a novel mouse model that enables precise genetic tracing and investigation of their turnover and longevity in specific tissues. By overcoming technical barriers, such as the lack of plasma cell-specific genetic tools these studies pave the way for in vivo manipulation of plasma cells within their niche. This breakthrough provides information on the dynamics of plasma cell populations but also holds promise for deciphering immune responses in various contexts, with far-reaching implications for both fundamental immunology research and clinical applications.

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